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The goal of Phase I of this clinical research study is to find the highest tolerable dose of ONC201 alone or in combination with low dose cytarabine (LDAC) that can be given to patients with relapsed or refractory AML, ALL, or MDS. The goal of Phase II of this study is to learn if the dose of ONC201 given alone or in combination with LDAC that is found in Phase I can help to control the disease.

The safety of the study drug will be studied in both phases of this study. This is the first study using ONC201 in humans.

ONC201 given alone or in combination with LDAC is in a very early stage of development for use in humans. Providing direct medical benefit to you is not the purpose of this study. While Phase II will look at the effectiveness of the study drug given alone or in combination with LDAC, the main purpose of this study is to learn about the safety of the drug.

ONC201 dosed orally once every three weeks. One cycle defined as 21 days (3 weeks).

Phase I: Cohorts consisting of one new patient per dosing level treated sequentially at rising dose levels starting at 125 mg. Enrollment at each dose level requires that all patients enrolled at the prior dose level have completed one cycle of treatment (21 days) and that dose level is deemed safe. Dose escalation continues until an maximum tolerated dose (MTD) is reached or dose level 5 is reached (625 mg), which will be declared the maximum administered dose (MAD).

Phase II: Starting dose is MTD dose from Phase I.

Drug: ONC201

Phase I Starting dose of ONC201: 125 mg by mouth once every 3 weeks.

Phase II Starting dose of ONC201: MTD from Phase I.

Experimental: Arm B: ONC201 Once Every 1 Week

ONC201 dosed orally once every 1 week. One cycle defined as 21 days (3 weeks).

Phase I: Cohorts consisting of one new patient per dosing level treated sequentially at rising dose levels starting at 125 mg. Enrollment at each dose level requires that all patients enrolled at the prior dose level have completed one cycle of treatment (21 days) and that dose level is deemed safe. Dose escalation continues until an maximum tolerated dose (MTD) is reached or dose level 5 is reached (625 mg), which will be declared the maximum administered dose (MAD).

Phase II: Starting dose is MTD dose from Phase I.

Drug: ONC201

Phase I Starting dose of ONC201: 125 mg by mouth once every 3 weeks.

Phase II Starting dose of ONC201: MTD from Phase I.

Experimental: Arm C: ONC201 On First Two Consecutive Days of Every Week

ONC201 dosed orally on the first two consecutive days of every week. One cycle defined as 21 days (3 weeks).

Phase I: Cohorts consisting of one new patient per dosing level treated sequentially at rising dose levels starting at 125 mg. Enrollment at each dose level requires that all patients enrolled at the prior dose level have completed one cycle of treatment (21 days) and that dose level is deemed safe. Dose escalation continues until an maximum tolerated dose (MTD) is reached or dose level 5 is reached (625 mg), which will be declared the maximum administered dose (MAD).

Phase II: Starting dose is MTD dose from Phase I.

Drug: ONC201

Phase I Starting dose of ONC201: 125 mg by mouth once every 3 weeks.

Phase II Starting dose of ONC201: MTD from Phase I.

Experimental: Arm D: ONC201 Once Daily

ONC201 dosed orally once daily. One cycle defined as 21 days (3 weeks).

Phase I: Cohorts consisting of one new patient per dosing level treated sequentially at rising dose levels starting at 125 mg. Enrollment at each dose level requires that all patients enrolled at the prior dose level have completed one cycle of treatment (21 days) and that dose level is deemed safe. Dose escalation continues until an maximum tolerated dose (MTD) is reached or dose level 5 is reached (625 mg), which will be declared the maximum administered dose (MAD).

Once the highest dose for Arm D (625 mg) are deemed safe (<2/6 DLTs) or the MTD is reached before that, then Phase I part of the study for Arm E will begin. The starting dose of ONC201 will be 625 mg or the MTD with the same schedule as that in Arm D. 3 + 3 algorithm will be applied for dose de-escalation.

MTD is defined as the highest dose level in which 6 patients have been treated with at most 1 instance of dose limiting toxicity (DLT). Toxicities defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLT defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and occurring during the first cycle on study that meets any of the following criteria:

CTCAE grade 3 AST (SGOT) or ALT (SGPT) for > 7 days

CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration

All other clinically significant NCI common terminology criteria that are CTCAE grade 3 or 4 (except for electrolyte disturbances responsive to correction within 24 h, diarrhea, nausea and vomiting that responds to standard medical care)

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

For Arms A, B, C, D patients must have relapsed or refractory acute leukemias or high-risk MDS for which no standard therapies are anticipated to result in a durable remission. For Arm E, in addition to patients with relapsed or refractory acute leukemias or high-risk MDS, patients with untreated high-risk MDS or acute leukemias will also be eligible provided they are not eligible for more intensive therapies.

Age >/=18 years.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device, such as a condom, diaphragm, or cervical/vault cap), for 16 weeks after the last dose of study drug, and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial. Nursing patients are excluded. Sexually active men must also use acceptable contraceptive methods for the duration of time on study and for at least 16 weeks after the last dose of study drug. Pregnant and nursing patients are excluded because the effects of ONC201on a fetus or nursing child are unknown.

Must be able and willing to give written informed consent.

The interval from prior treatment to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. If the patient is on hydroxyurea to control peripheral blood leukemic cell counts, the patient must be off hydroxyurea for at least 24 hours before initiation of treatment on this protocol. Persistent clinically significant toxicities from prior therapy must not be greater than grade 1.

Patients must have the following clinical laboratory values unless considered due to leukemic organ involvement: (1) Serum creatinine < 2.0 mg/dl; (2) Total bilirubin </= 1.5 x the upper limit of normal (ULN) unless considered due to Gilbert's syndrome; (3) Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) </= 3 x the ULN unless considered due to organ leukemic involvement.

Patients with known central nervous system (CNS) disease are allowed if there is no evidence of active CNS disease as documented by negative imaging or spinal fluid analysis carried out at least 2 weeks prior to study drug administration. Information obtained from standard of care historical data will be used for this purpose.